Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastrin stimulates transcription of the human histidine decarboxylase (HDC) gene through binding to the G-protein-coupled cholecystokinin-B/gastrin receptor. We have explored the possibility that mitogen-activated protein kinase cascades play a role in mediating the effects of gastrin on transcription in a gastric cancer (AGS-B) cell line. Gastrin and phorbol 12-myristate 13-acetate (PMA) treatment of AGS-B cells was found to increase the phosphorylation of tyrosine residues of extracellular signal-regulated kinases (ERKs) 1 and 2 and increase ERK activity as determined by the in vitro phosphorylation of myelin basic protein. Reporter gene assays also demonstrated that gastrin and PMA stimulated Elk-1- and c-Myc-dependent transactivation, consistent with gastrin- and PMA-induced activation of ERKs. Overexpression of wild type ERK-1 and ERK-2 or activation of endogenous ERKs using activated MEK-1 (mitogen-activated protein kinase kinase or ERK kinase) overexpression stimulated HDC promoter activity in a dose-dependent fashion. Interruption of the ERK-related pathway using expression vectors for kinase-deficient ERKs or an ERK-specific phosphatase (PAC-1) blocked gastrin- and PMA-stimulated HDC promoter activity. In contrast, inhibition of the Jun kinase pathway using an interfering dominant negative SEK-1 (stress-activated protein kinase/ERK-1) mutant did not inhibit HDC promoter activity. Furthermore, whereas gastrin stimulated phosphorylation of Shc proteins and association with Grb2, activation of the HDC promoter was not influenced by expression of dominant negative Ras (N15 or N17) proteins. However, gastrin stimulated Raf-1 kinase activity, and activation of the HDC promoter was blocked by coexpression of a dominant negative Raf-1 construct. Overall, these data demonstrate that gastrin regulates HDC transcription in a Rafdependent, Ras-independent fashion predominantly through activation of the ERK-related pathway.
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PMID:Gastrin and phorbol 12-myristate 13-acetate regulate the human histidine decarboxylase promoter through Raf-dependent activation of extracellular signal-regulated kinase-related signaling pathways in gastric cancer cells. 934 Nov 40

Human gastric cancer cells were used to examine the trophic effect of the muscarinic m3 receptor subtype. Expression of the m3 receptor was detected in five of eight cell lines examined, MKN-1, 7, 28, 74, and TMK-1 cells. An increase in intracellular Ca2+ in response to carbachol was observed in more than 90% of TMK-1 cells, allowing us to use these cells in the following experiments. Western blot analysis showed that carbachol predominantly phosphorylated tyrosine in a 100-kDa protein. While mitogen-activated protein (MAP) kinase activity in the presence of 100 microM carbachol or 10 ng/ml transforming growth factor (TGF)alpha was augmented to 15- to 60-fold of the baseline level for 5min, the activation was transient. Pretreatment of the cells with 1 microM phorbol 12-myristate 13-acetate abolished carbacol-induced MAP kinase activation, whereas no suppression was observed in the presence of 500 nM Calphostin C (Kyowa Medex, Tokyo Japan), a specific protein kinase C inhibitor. No DNA synthesis or cell proliferation was observed in the presence of carbachol. These results indicate that stimulation of the m3 subtype leads to tyrosine phosphorylation and MAP kinase activation, but is unlikely to have trophic effects in gastric mucosal cells.
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PMID:Functional muscarinic m3 receptor expressed in gastric cancer cells stimulates tyrosine phosphorylation and MAP kinase. 1021 13

The human histidine decarboxylase gene is regulated by gastrin through a cis-acting element known as the gastrin response element (GAS-RE) that was initially localized to a site (+2 to +24) downstream of the transcriptional start site. Electrophoretic mobility shift assays using sequentially deleted DNA probes and nuclear extracts from AGS-B gastric cancer cells showed that the GAS-RE is actually composed of two overlapping binding sites (GAS-RE1, +1 to +19; and GAS-RE2, +11 to +27) that bind distinct nuclear factors. Reporter gene assays demonstrated that each element alone could confer gastrin responsiveness, but the presence of both elements was required for complete gastrin response. Stimulation of AGS-B cells with gastrin for 10-20 min resulted in a >2-fold increase in factor binding. The binding was inhibited by pretreatment of AGS-B cells with cycloheximide and the MEK1 inhibitor PD98059, indicating a requirement for protein synthesis and also indicating that activation occurs through the MEK/mitogen-activated protein kinase pathway. UV cross-linking and Southwestern blot analysis showed that GAS-RE1 bound a 52-kDa protein, whereas GAS-RE2 bound a 35-kDa protein. Hence, activation of histidine decarboxylase gene promoter activity by gastrin is most likely mediated by two separate nuclear factors.
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PMID:Activation of human histidine decarboxylase gene promoter activity by gastrin is mediated by two distinct nuclear factors. 1040 43

Apoptois is an important determinant in the sensitivity to chemotherapeutic agents in gastric cancer cells. In this study, we examined whether the introduction of the bax gene into MKN45 gastric cancer cells could enhance the sensitivity to chemotherapeutic agents in association with apoptosis. Apoptosis in the bax-transfected gastric cancer cells was enhanced following the treatment of various chemotherapeutic agents including adriamycin (ADM), cisplatin (CDDP), etoposide (VP-16) and taxotere (TXT) as compared to those of neo gene-transfected cells. The enhancement of apoptosis was coincident with the increase of sensitivity in the ratio of IC50 value, that was 1.3-fold in ADM, 4.4-fold in CDDP, 4.6-fold in VP-16 and 2.5-fold in TXT, respectively. Further, the enhancement of apoptosis in the bax-transfected gastric cancer cells was associated with the activation of c-Jun N-terminal kinase 1 (JNK 1) and caspase 3 (CPP32). The increases of sensitivities to these agents in the bax-transfected cells were also demonstrated in in vivo experiments using the tumor cells transplanted into nude mice. The tumor growth in the bax-transfected cells was significantly suppressed following the treatment of CDDP or VP-16 compared to that of neo-transfected cells (p < 0.05). These results indicated that, the bax gene might play a critical role in determination of sensitivity to chemotherapeutic agent in gastric cancer cells in vivo, and that the activation of JNK 1 and CPP32 might be involved in the signal transduction pathways leading to apoptosis.
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PMID:Enhancement of chemotherapeutic agents induced-apoptosis associated with activation of c-Jun N-terminal kinase 1 and caspase 3 (CPP32) in bax-transfected gastric cancer cells. 1076 93

Helicobacter pylori induces cellular proliferation in host cells, but the mechanism remains unclear. Thus, we examined the effect of H. pylori on cyclin D1, an important regulator of the cell cycle, especially in relation to intracellular signaling pathways. In a Northern blot analysis, cyclin D1 transcription in gastric cancer (AGS) cells was enhanced by coculture with H. pylori strain TN2 in a time-dependent and multiplicity-of-infection-dependent manner. An isogenic mutant form of vacA also increased cyclin D1 transcription, but mutant forms of cagE or the entire cag pathogenicity island did not enhance cyclin D1 transcription. These effects were confirmed with a luciferase assay of the cyclin D1 promoter (pD1luc). Cyclin D1 promoter activation by H. pylori was inhibited by MEK inhibitors (U0126 and PD98059), indicating that the mitogen-activated protein kinase pathway may be involved in intracellular signal transduction. In contrast, transfection of a reporter plasmid having any point mutations of the NF-kappaB binding sites in the promoter (pD1-kappaB1M, pD1-kappaB2M, or pD1-kappaB1/2M) or cotransfection of dominant negative IkappaBalpha did not affect cyclin D1 activation by H. pylori. In conclusion, H. pylori activates cyclin D1 through the mitogen-activated protein kinase pathway and not through NF-kappaB activation in AGS cells. This activation of cyclin D1 is partly dependent on the cag pathogenicity island but not on vacA.
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PMID:Helicobacter pylori activates the cyclin D1 gene through mitogen-activated protein kinase pathway in gastric cancer cells. 1134 65

Surgical treatment of gastric cancer patients is dismal because advanced tumor is often noted at diagnosis. In order to obtain better adjuvant therapy for gastric cancer patients after operation, it is important to understand the mechanism of invasion and metastasis. It is well known that binding of hepatocyte growth factor (HGF) to its receptor (c-Met) regulates gastric cancer progression and metastasis. Recently, HGF was found to up-regulate the expression of cyclooxygenase-2 (COX-2) gene and increase prostaglandin (PG)synthesis in gastric mucosa cells. Over-expression of COX-2 and increased PG secretion have also been found to be involved in the growth and metastasis of gastric cancer. These results together suggest that the signaling pathway of HGF and c-Met may be mediated through ERK2 activation, up-regulation of COX-2 and increased production of PGE(2)in gastric cancer cells. In view of the fact that c-Met is over-expressed in the majority of gastric cancer patients with poor prognosis, COX-2 specific inhibitors may provide beneficial effects in these patients.
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PMID:Nonsteroidal anti-inflammatory drugs for treatment of advanced gastric cancer: cyclooxygenase-2 is involved in hepatocyte growth factor mediated tumor development and progression. 1160 79

Resveratrol, a polyphenolic phytochemical present in berries, grapes, and wine, has emerged as a promising chemopreventive candidate. Because there is scant information regarding natural agents that prevent, suppress, or reverse gastric carcinogenesis, the aim of the present study was to determine the chemopreventive potential of resveratrol against gastric cancer by investigating cellular and molecular events associated with resveratrol treatment of human gastric adenocarcinoma cells. We determined the action of resveratrol on cellular function and cellular integrity by measuring DNA synthesis, cellular proliferation, cell cycle distribution, cytolysis, apoptosis, and phosphotransferase activities of two key signaling enzymes, protein kinase C (PKC) and mitogen-activated protein kinases (ERK1/ERK2), in human gastric adenocarcinoma KATO-III and RF-1 cells. Resveratrol inhibited [3H]thymidine incorporation into cellular DNA of normally proliferating KATO-III cells and of RF-1 cells whose proliferation was stimulated with carcinogenic nitrosamines. Treatment with resveratrol arrested KATO-III cells in the G(0)/G(1) phase of the cell cycle and eventually induced apoptotic cell death, but had a minimal effect on cell lysis. Resveratrol treatment had no effect on ERK1/ERK2 activity but significantly inhibited PKC activity of KATO-III cells and of human recombinant PKCalpha. Results indicate that resveratrol has potential as a chemopreventive agent against gastric cancer because it exerts an overall deactivating effect on human gastric adenocarcinoma cells. Resveratrol-induced inhibition of PKC activity and of PKCalpha, without any change in ERK1/ERK2 activity, suggests that resveratrol utilizes a PKC-mediated mechanism to deactivate gastric adenocarcinoma cells.
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PMID:Resveratrol-induced inactivation of human gastric adenocarcinoma cells through a protein kinase C-mediated mechanism. 1170 3

The M(r) 78,000 glucose-regulated protein (GRP78) can be induced by physiological stresses such as glucose deprivation and hypoxia. In solid tumors, hypoxia can promote malignant progression and confer resistance to irradiation and chemotherapy by altering gene expression. Here, we investigated the molecular mechanisms and signaling pathway involved in the late and prolonged induction of the GRP78 gene by hypoxia in a human gastric cancer cell line, MKN28. Nuclear run-on assays and mRNA stability measurements revealed that transcriptional activation, not stabilization of mRNA, contributed to the dramatic induction of GRP78 gene under hypoxia. Induction of GRP78 by chronic hypoxia was completely abolished by pretreatment with PD98059 [a specific inhibitor of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK1)] or by overexpression of a dominant-negative MEK1 mutant, demonstrating a direct involvement of ERK in the induction of transcription at the GRP78 promoter under these conditions. Furthermore, hypoxia increased the transcriptional activity of a 12-O-tetradecanoylphorbol-13-acetate response element-like motif on the GRP78 promoter and increased the abundance and DNA binding activity of AP-1 complex composed of c-Jun and c-Fos. A selective protein kinase C (PKC) inhibitor, GF109203X, inhibited the induction of GRP78 gene expression as well as the activities of both ERK and Raf-1. Among six PKC isoforms expressed in MKN28 cells, PKC-epsilon expression level and kinase activity were increased by hypoxia. Transfection of MKN28 cells with a dominant-negative PKC-epsilon blocked the induction of GRP78 through ERK by hypoxia, indicating that PKC-epsilon directly participated in GRP78 induction under hypoxia. Taken together, this study shows that a PKC-epsilon-Raf-1-MEK-ERK-AP1 signaling cascade acts on a 12-O-tetradecanoylphorbol-13-acetate response element-like element to mediate hypoxia-induced GRP78 expression in human gastric cancer cells. We also confirmed in vivo the overexpression of GRP78 in surgical specimens of human primary gastric tumors.
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PMID:Induction of glucose-regulated protein 78 by chronic hypoxia in human gastric tumor cells through a protein kinase C-epsilon/ERK/AP-1 signaling cascade. 1171 66

Apoptosis plays a critical role in maintaining genomic integrity by selectively removing the most heavily damaged cells from the population. Reactive oxygen species (ROS) and certain inflammatory cytokines are always elevated during the human carcinogenic process. However, the biological significance of the interplay between ROS and inflammatory cytokine remains elusive. This study demonstrates that interleukin-6 (IL-6) effectively protects gastric cancer cells from the apoptosis induced by hydrogen peroxide (H(2)O(2)). The cell death signaling JNK pathway elicited by H(2)O(2) is also inhibited by IL-6. We further found that Mcl-1, but not other Bcl-2 family members, was up-regulated by IL-6, by a substantial level over 24 h. We further transfected a mcl-1 expression vector, pCMV-mcl-1, into the AGS cells, and successfully obtained several mcl-1-overexpressing clones. Flow cytometric analysis shows that these mcl-1-overexpressing AGS cells are more resistant to the apoptosis induced by H(2)O(2) when compared with the neo control AGS cells. Consistently, the activation of the JNK pathway induced by H(2)O(2) is also blocked in mcl-1-overexpressed cells. These results indicate that the anti-apoptotic effect of IL-6 is, at least in part, due to the up-regulation of mcl-1. To our surprise, either IL-6 exposure or mcl-1 overexpression fails to reduce the level of intracellular peroxides in the AGS cells triggered by H(2)O(2). This study also determined the level of 8-hydroxydeoxyguanosine (8-OH-dGua), an indicator for oxidative DNA lesions in IL-6-treated or mcl-1-overexpressed AGS cells after treatment with H(2)O(2). Notably, our results indicate that a majority of the 8-OH-dGua is efficiently removed in the AGS cells without IL-6 treatment, whereas only approximately 50% of the 8-OH-dGua was repaired in the IL-6-treated AGS cells after 24 h. Similarly, approximately 60-70% of the 8-OH-dGua also failed to repair and was retained in the genomic DNA of the mcl-1 transfectants. Results in this study provide a novel mechanism by which up-regulation of the Mcl-1 protein by IL-6 may enhance the susceptibility to H(2)O(2)-induced oxidative DNA lesions by overriding apoptosis.
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PMID:IL-6 inhibits apoptosis and retains oxidative DNA lesions in human gastric cancer AGS cells through up-regulation of anti-apoptotic gene mcl-1. 1175 24

Epidemiological studies have demonstrated a strong association between Helicobacter pylori infection and gastric cancer. However, there have been few detailed studies on the mechanism of cellular proliferation by H. pylori. Thus, we examined activation of the proto-oncogene c-fos to elucidate the underlying mechanism of cell proliferation caused by H. pylori. Activation of c-fos was evaluated in human gastric cancer cells (TMK1) by Northern blot and reporter assays with deletion analysis of the c-fos transcriptional control region. c-fos promoter activation and transcription were enhanced when cocultured with cag-positive strains. H. pylori-mediated c-fos promoter activation was inhibited by MEK1/2 inhibitor (U0126). The deletion analysis indicated that serum response element (SRE) was required for the activation of c-fos by H. pylori. In conclusion, c-fos promoter activation and transcription were enhanced through the activation of extracellular signal-regulated kinases (ERK)/mitogen-activated protein kinase (MAPK) cascade in gastric cancer cells when cocultured with H. pylori possessing intact cag PAI. SRE is required for the activation of c-fos by H. pylori. These results suggest a direct involvement of H. pylori infection in cellular proliferation, which may play a role in neoplastic transformation.
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PMID:Helicobacter pylori activates the proto-oncogene c-fos through SRE transactivation. 1186 45


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